Aldosterone is a specific ligand for a mineral corticoid receptor (hereinafter also referred to as MR) and one of mediators for renin-angiotensin-aldosterone system (RAAS). Aldosterone is mainly produced in an adrenal gland and has been considered as a mineral corticoid hormone which regulates metabolism of sodium and water by affecting a distal tubule of a kidney. In a recent study, it has been shown that aldosterone is produced in various tissues such as a heart, blood vessels and a brain, and that the MR is widely distributed to tissues such as cardiovascular tissues. Therefore, aldosterone is recognized as a risk hormone which exerts various deleterious effects on cardiovascular tissues (e.g., heart fibrosis and necrosis; enhanced effect of catecholamine, and decrease of a baroreceptor reaction), in addition to, as an exacerbation factor for hypertension.
A means of blocking an effect of aldosterone is an effective method for treating, for example, cardiovascular diseases associated with said aldosterone and a receptor thereof. An MR antagonist (e.g., eplerenone or spironolactone), which has an affinity for MR and blocks its receptor function, has already been used for treating hypertension. In large clinical tests (RALES and EPHESUS), it was confirmed that, by combined administration of the MR antagonist and a conventional therapeutic agent such as an ACE inhibitor, a hospitalization rate, and a mortality rate caused by cardiac diseases in patients with severe heart failure were significantly decreased, and that prognosis of patients with acute myocardial infarction was significantly improved (non-patent documents 1 and 2).
On the other hand, the MR antagonist (e.g., spironolactone or eplerenone) has specific serious adverse effects (e.g., hyperkalemia). In addition, use of spironolactone is often associated with gynecomastia, menstrual disorders, erectile dysfunction, and the like. Accordingly, it is desired to develop a compound for treating a disease associated with aldosterone which has no such adverse effect and has higher safety. An aldosterone synthetase (Cyp11B2) inhibitor has been proposed as an alternative approach from the point of view above (i.e., another approach for blocking or reducing an effect of aldosterone).
Cyp11B2 is a cytochrome P450 enzyme and is known as an enzyme which catalyzes a series of reactions leading from 11-deoxycorticosterone (i.e., an aldosterone precursor) to aldosterone. Cyp11B2 is mainly expressed in an adrenal cortex spherical layer and a level of plasma aldosterone is regulated by enzymic activity of Cyp11B2 present in an adrenal gland. In addition, it has been confirmed that aldosterone was expressed in some tissues other than adrenal glands such as a cardiovascular system, a kidney, adipose tissues and a brain, as well as, it has drawn attention that organ disorders were associated with aldosterone, which was locally produced in each organ. It has been reported that an inhibitor of Cyp11B2 inhibited production of aldosterone through studies using the enzyme and cells in culture, and that the inhibitor had a suppressive effect against production of aldosterone and any therapeutic effect through studies using various experimental animal models. Further, it has been confirmed that a Cyp11B2 inhibitor showed a plasma aldosterone level-lowering effect and a urine aldosterone level-lowering effect as well as an antihypertensive effect in hypertensive patients and primary aldosteronism patients (non-patent documents 3 and 4). A highly feasible approach for establishing an effective therapy for various diseases associated with aldosterone is to find a means for inhibiting a biosynthesis route of aldosterone.
Previously, although aryl pyridine compounds (patent document 1), benzimidazol substituted pyridine compounds (patent document 2), and the like are known as a compound having an aldosterone synthetase (Cyp11B2) inhibitory activity, it has not been reported that a 1,2,4-triazine compound such as a compound of the present invention had an aldosterone synthetase inhibitory activity. In addition, 1,2,4-triazine compounds of the following formulae (a), (b) and (c):
are listed in a commercial compound database (Registry) as Accession Nos: 1070398-58-1, 1069628-74-5, 1060824-77-2. However, it is not clarified what kind of physiological activity these compounds have.